A class of proteins recently has been identified, the members of which are true tissue morphogenic proteins. The members of this class of proteins are characterized as competent for inducing the developmental cascade of cellular and molecular events that culminate in the formation of new organ-specific tissue, including any vascular and connective tissue formation as required by the naturally occurring tissue. Specifically, the morphogens are competent for inducing all of the following biological functions in a morphogenically permissive environment: (1) stimulating proliferation of progenitor cells; (2) stimulating differentiation of progenitor cells; (3) stimulating the proliferation of differentiated cells and (4) supporting the growth and maintenance of differentiated cells. For example, the morphogenic proteins can induce the full developmental cascade of bone tissue morphogenesis, including the migration and proliferation of mesenchymal cells, proliferation and differentiation of chondrocytes, cartilage matrix formation and calcification, vascular invasion, osteoblast proliferation, bone formation, bone remodeling, and hematopoietic bone marrow differentiation. These proteins also have been shown to induce true tissue morphogenesis of non-chondrogenic tissue, including dentin, liver, and nerve tissue.
A particularly useful tissue morphogenic protein is human OP-1 (Osteogenic Protein-1), described in U.S. Pat. No. 5,011,691; U.S. Pat. No. 5,266,683 and Ozkaynak et al. (1990) EMBO J. 9: 2085-2093. Species homologues identified to date include mouse OP-1 (see U.S. Pat. No. 5,266,683) and the Drosophila homologue 60A, described in Wharton et al. (1991) PNAS 88:9214-9218). Other closely related proteins include OP-2 (Ozkaynak (1992) J. Biol. Chem. 267:25220-25227 and U.S. Pat. No. 5,266,683); BMP5, BMP6 (Celeste et al. (1991) PNAS 87:9843-9847) and Vgr-1 (Lyons et al. (1989). These disclosures are incorporated herein by reference.
It previously has been contemplated that these tissue morphogens can be administered to an animal to regenerate lost or damaged tissue. Alternatively, one can envision administering a molecule capable of modulating expression of the endogenous tissue morphogen as a means for providing morphogen to a site in vivo.
It is an object of this invention to provide compositions and methods of screening compounds which can modulate expression of an endogenous tissue morphogen, particularly OP-1 and closely related genes. The compounds thus identified have utility both in vitro and in vivo. Useful compounds contemplated include those capable of stimulating transcription and/or translation of the OP-1 gene, as well as compounds capable of inhibiting transcription and/or translation of the OP-1 gene.
These and other objects and features of the invention will be apparent from the description, drawings and claims which follow.